非小细胞肺癌耐药相关基因表达与细胞凋亡相关性及其临床意义

目的探讨非小细胞肺癌（Non－Small CellLung Cancer，NSCLC）多种耐药相关基因MRP、MDR1、c－erbB－2表达与细胞凋亡及相关基因bc1－2、c－myc的关系与意义。方法RT－PCR、免疫组化分析多种耐药、凋亡相关基因mRNA及蛋白表达，原位末端标记Terminaldeoxynucleotidyltransferase（TdT）－mediatedbiotind UT Pnickend－labeling，TUNEL检测凋亡细胞。结果63例NSCLCMRP、MDR1、c－erbB－2、bc1－2、c－mycmRNA阳性率分别为81．0％（51／63）、38．1％（24／63）、47．6％（30／63）、65．1％（41／63）、76．2％（48／63），均高于相应的蛋白表达水平（分别为74．6％、34．9％、46．0％、61．9％、71．4％），二者具高度相关性（相关系数r＝＋0．76以上，P＜0．02），5例癌旁组织仅2例c－myc弱阳性，余皆阴性。c－myc、bc1－2与c－erbB－2呈正相关（r＝＋0．54，P＝0．001，r＝＋0．48，P＝0．023），与MRP、MDR1无相关性。凋亡指数与bc1－2负相关（r＝－0．58，P＝0．017），与MRP、MDR1、c－erbB－2、c－myc无相关性；腺癌及鳞癌化疗有效组凋亡指数均数（27．2±2．1，30．5±1．8）高于化疗无效组（9．4±1．3，12．6±2．4）（P＝0．001，P＝0．004），bcl－2、MRP、c－erbB－2阳性率（31．8％，40．9％，22．9％）低于化疗无效组（77．4％，90．3％，67．5％）（P＝0．03，P＝0．01，P＝0．01），但两组间MDR1、c－myc表达无显著差异（P＝0．06，P＝0．28）。三种以上耐药及凋亡相关基因共表达者中位生存期（8．6个月）明显短于3种以下共表达者（15．5个月）（P＝0．01）。结论NSCLC耐药不仅与多种耐药基因有关，亦涉及细胞凋亡及其相关基因表达，多种耐药及凋亡相关基因共表达与生存期有关。

The Correlation between Multidrug Resistance Related Gene and Apoptosis of Lung Cancer and Its Clinical Significance

Objective： To study the correlation between the expressions ofmultidrug resistance （MDR） gene MRP， MDR1， c－erbB－2 and apoptosis related genes bcl－2， c－myc， and its clinical significance in non－small cell lung cancer． Methods： RT－PCR and immunohistochemistry were used to examine expressions of mRNA and protein of the above mentioned genes， apoptotic cells were evaluated by terminal deoxynucleotidyl transferase （TDT）－mediated biotin dUTP nick end－labeling （TUNEL）， Results： The levels of MRP， MDR1， c－erbB－2， bcl－2 and c－myc mRNA （81．0％， 38．1％， 47．6％， 65．1％， 76．2％） were higher than the levels of their corresponding proteins （74．6％， 34．9％， 46．0％， 61．9％， 71．4％ respectively）， and their significant positive associations were found between mRNA levels and their protein expression （r＞0．764，P＜0．02） in 63 analysed samples positive correlations were demonstrated between c－myc and c－erbB－2 （r＝＋0．54，P＝0．001）， bcl－2 and c－erbB－2 （r＝＋0．48，P＝0．023）． No significant correlation was found between bcl－2 and MRP or MDR1 in NSCLC． Apoptotic index was observed to be inversely correlated with bcl－2 expression （r＝－0．58，P＝0．017） but not to be associated with MRP， MDR1， c－erbB－2 or c－myc． There were higher apoptotic index and lower expressions of MRP， bcl－2 and c－erbB－2 in the effective groups to chemotherapy than in the ineffective groups （P＜0．05）． Patients with expressions of more than three MDR and／or apoptosis related genes had shorter median survival time （P＝0．01）． Conclusion： Multidrug resistance in NSCLC may be involved in the co－operation of multiple MDR and／or apoptosis related genes， and which relates to median survival time．